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Introduction: Estimation of residual apixaban plasma concentrations may be requested in the management of emergencies. This study aims at assessing the performance of specific anti-Xa assays calibrated with apixaban on real-life samples with low apixaban plasma concentrations (®-Liquid Anti-Xa assay (STA ® LAX) and the low and normal procedures of the Biophen ®Direct Factor Xa Inhibitors (DiXaI) assay was tested on 134 blood samples, collected from patients on apixaban, wherefrom 74 patients received LMWH after apixaban cessation. The results were compared with the liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) measurements. Results: The Biophen ®DiXaI, Biophen ®DiXaI LOW, and STA ®LAX showed very good correlation with LC-MS/MS measurements in patients without LMWH administration (Spearman r.95,.99, and.98, respectively). Their limits of quantitation were defined at 48, 24, and 12 ng/mL, respectively. The Bland-Altman test measured mean bias (SD) at 5.6 (13.1), −2.5 (5.0), and −0.8 (6.1) ng/ml, respectively. The Spearman r of the Biophen ®DiXaI decreased to 0.64 in presence of low apixaban concentrations. The Spearman r of the Biophen ®DiXaI LOW and STA ®LAX decreased to 0.39 and 0.26, respectively, in presence of LMWH. Conclusions: The accuracy of the low methodologies (Biophen ®DiXaI LOW and STA ®LAX) is slightly improved for low apixaban plasma concentrations, compared with the normal procedure of Biophen ®DiXaI. The interference of LMWH on the low methodologies is measurable, however, less important than the previously reported interference of LMWH on rivaroxaban calibrated specific anti-Xa assays.

La COVID-19 est une maladie infectieuse émergente virale causée par la souche de coronavirus SARSCoV-2. Après presque deux années de pandémie, les cliniciens ont beaucoup progressé dans les connaissances des manifestations cliniques de la maladie, notamment en mettant en avant la place du glycocalyx endothélial. Ce dernier est une structure complexe micro-fibrillaire située au pôle apical de la cellule endothéliale, constituant la barrière histologique entre la cellule et la lumière vasculaire et se comportant comme un organe à part entière. L’étude physiopathologique de ce dernier a permis de mettre en évidence l’intérêt de celui-ci dans la compréhension de la COVID-19 et de ses complications. Cette revue a donc pour but d’appréhender cette maladie sous un angle différent et se propose de résumer les données pertinentes pour le clinicien que nous avons apprises depuis deux ans.

Background: Thrombin generation testing has been used to provide information on the coagulation phenotype of patients. The most used technique is the calibrated automated thrombogram (CAT) but it suffers from a lack of standardization, preventing its implementation in routine. The ST Genesia is a new analyzer designed to assess thrombin generation based on the same principle as the CAT. Unlike the CAT system, the ST Genesia is a benchtop, fully automated analyzer, able to perform the analyses individually and not by batch, with strict control of variables such as temperature and volumes, ensuring, theoretically, maximal reproducibility. Objectives: This study aimed at assessing the performance of the STG-DrugScreen application on the ST Genesia analyzer. We also aimed at exploring stability of plasma samples after freezing and defining a reference normal range. Results: Results demonstrated the excellent interexperiment precision of the ST Genesia and confirmed that the use of a reference plasma helps reducing the inter-experiments variability. Stability revealed that plasma samples are stable for at least 11 months at −70°C or lower, except for those containing low molecular weight heparins which have to be tested within 6 months. Freezing had no effect on the majority of thrombin generation parameters except on time to peak. Conclusions: Our results suggest an easy implementation of thrombin generation with the use of ST Genesia in the routine laboratory. This will facilitate the design of multicentric studies and enable the establishment of reliable and evidence-based thresholds, which may improve the management of patients treated with anticoagulants.

Purpose. Airway stenting offers good palliation and improves the quality of life in patients with inoperable bronchotracheal stenosis. However, in some cases, the management of stenting can be life-threatening. Hence, a strategy for maintaining oxygenation and hemodynamic stability should be anticipated to avoid critical situations. Herein, we report the use of extracorporeal membrane oxygenation (ECMO) in bronchotracheal stenting management to secure oxygenation and facilitate interventions. Methods. We retrospectively reviewed all patients who underwent rigid bronchoscopy under ECMO support for the management of bronchotracheal stenting at CHU UCL Namur hospital (Belgium), between January 2009 and December 2019. Results. We included 14 bronchoscopy cases performed on 11 patients (3 patients underwent 2 bronchoscopies) in this study; 12 were performed on males and 2 on females. The median age was 54 years. There were 11 benign and 3 malignant etiologies for the central airway obstruction/stenosis. Eight cases were supported by venovenous ECMO and six by venoarterial ECMO. The median ECMO time was 267 minutes. The weaning of ECMO support was successful in all cases. In most cases, the procedures were performed effectively and safely. Only two local complications caused by the cannulation of ECMO were reported, and anticoagulation was adapted to avoid bleeding at the operating site and clot formation in the system. Conclusion. Elective ECMO support was helpful and safe for the high-risk management of bronchotracheal stenting with rigid bronchoscopy and was not associated with any additional significant complications.

P2Y12 inhibitor discontinuation is essential before most surgical interventions to limit bleeding complications. Based on pharmacokinetic data, fixed discontinuation durations have been recommended. However, as platelet function recovery is highly variable among patients, a more individualized approach based on platelet function testing (PFT) has been proposed. The aim of this retrospective single-centre study was to determine whether PFT using whole blood adenosine diphosphate&ndash, multiple electrode aggregometry (ADP&ndash, MEA) was associated with a safe reduction of preoperative waiting time. Preoperative ADP&ndash, MEA was performed for 29 patients on P2Y12 inhibitors. Among those, 17 patients underwent a coronary artery bypass graft. Twenty one were operated with an ADP&ndash, MEA &ge, 19 U (quantification of the area under the aggregation curve), and the waiting time was shorter by 1.6 days (median 1.8 days, IQR 0.5&ndash, 2.9), by comparison with the current recommendations (five days for clopidogrel and ticagrelor, seven days for prasugrel). Platelet function recovery was indeed highly variable among individuals. With the 19 U threshold, high residual platelet inhibition was associated with perioperative platelet transfusion. These results suggest that preoperative PFT with ADP&ndash, MEA could help reduce waiting time before urgent surgery for patients on P2Y12 inhibitors.

Background Guidelines recommend performing atrial fibrillation (AF) catheter ablation without interruption of a direct oral anticoagulants (DOACs) and to administer unfractionated heparin (UFH) for an activated clotting time (ACT) ≥300 seconds, by analogy with vitamin K antagonist (VKA). Nevertheless, pharmacological differences between DOACs and VKA, especially regarding ACT sensitivity and UFH response, prevent extrapolation from VKA to DOACs. Hypothesis The level of anticoagulation at the time of the procedure in uninterrupted DOAC-treated patients is unpredictable and would complicate intraprocedural UFH administration and monitoring. Methods This prospective study included interrupted DOAC-treated patients requiring AF ablation. Preprocedural DOAC concentration ([DOAC]), intraprocedural UFH administration, and ACT values were recorded. A cohort of DOAC-treated patients requiring flutter catheter ablation was considered to illustrate [DOAC] without DOAC interruption. Results Forty-eight patients underwent AF and 14 patients underwent flutter ablation, respectively. In uninterrupted DOAC-treated patients, [DOAC] ranged from ≤30 to 466 ng/mL. When DOAC were interrupted, from 54 to 218 hours, [DOAC] were minimal (maximum: 36 ng/mL), preventing DOAC-ACT interference. Anyway, ACT values were poorly correlated with UFH doses (R 2 = 0.2256). Conclusions Our data showed that uninterrupted DOAC therapy resulted in an unpredictable and highly variable initial level of anticoagulation before catheter ablation. Moreover, even with DOAC interruption preventing interference between DOAC, UFH, and ACT, intraprocedural UFH monitoring was complex. Altogether, our exploratory results call into question the appropriateness of transposing UFH dose protocols, as well as the relevance of ACT monitoring in uninterrupted DOAC-treated patients.

Aims Patients receiving direct oral anticoagulants (DOACs) frequently undergo elective invasive procedures. Their management is challenging. We aimed to determine the optimal duration of DOAC discontinuation that ensures a minimal anticoagulant effect during the procedure. Methods and results This prospective multicentre study included 422 DOAC-treated patients requiring an invasive procedure. Pre-procedural DOAC concentration ([DOAC]) and routine haemostasis assays were performed to determine i/the proportion of patients who achieved a minimal pre-procedural [DOAC] (≤30 ng/mL) according to the duration of DOAC discontinuation, ii/the predictors of minimal [DOAC] and, iii/the ability of routine assays to predict minimal [DOAC]. Lastly, we assessed the predictors of peri-procedural bleeding events. The duration of DOAC discontinuation ranged from 1 to 218 h and pre-procedural [DOAC] from ≤30 to 527 ng/mL. After a 49-72-h discontinuation, 95% of the [DOAC] were ≤30 ng/mL. A 72-h discontinuation predicted concentrations ≤30 ng/mL with 91% specificity. In multivariable analysis, duration of DOAC discontinuation, creatinine clearance

INTRODUCTION: Andexanet alfa is a recombinant modified factor Xa protein that has been developed to reverse factor Xa inhibitors. Since May 2018, the FDA has approved its utilization in patients treated with apixaban and rivaroxaban in case of life-threatening or uncontrolled bleeding. On 28 of February 2019, the Committee for Medicinal Products for Human Use adopted a positive opinion, recommending the granting of a conditional marketing authorization for andexanet alfa in Europe. Area covered: The authors provide an overview of andexanet alfa development and its pharmacokinetic and pharmacodynamic properties. The results of the clinical phase III trial ANNEXA as well as current limitations related to andexanet alfa are also discussed. Expert opinion: Although phase I and II studies have proven that andexanet alfa can be effective in reversing the effect of factor Xa inhibitors, its efficacy in major bleeding patients has only been shown for apixaban and rivaroxaban, without any comparator group. Well-designed studies comparing the efficacy and safety of andexanet alfa to other reversal strategies are required to confirm preliminary data. The benefit of andexanet alfa in specific settings needs to be investigated and its use in clinical practice needs to be facilitated by the implementation of international guidelines.

The indications for rigid bronchoscopy for interventional pulmonology have increased and include stent placements and transbronchial cryobiopsy procedures. The shared airway between anesthesiologist and pulmonologist and the open airway system, requiring specific ventilation techniques such as jet ventilation, need a good understanding of the procedure to reduce potentially harmful complications. Appropriate adjustment of the ventilator settings including pause pressure and peak inspiratory pressure reduces the risk of barotrauma. High frequency jet ventilation allows adequate oxygenation and carbon dioxide removal even in cases of tracheal stenosis up to frequencies of around 150 min−1; however, in an in vivo animal model, high frequency jet ventilation along with normal frequency jet ventilation (superimposed high frequency jet ventilation) has been shown to improve oxygenation by increasing lung volume and carbon dioxide removal by increasing tidal volume across a large spectrum of frequencies without increasing barotrauma. General anesthesia with a continuous, intravenous, short-acting agent is safe and effective during rigid bronchoscopy procedures.

Introduction.We herein report our experience with new fully covered self-expanding metallic stents in the setting of inoperable recurrent benign tracheobronchial stenosis.Methods.Between May 2010 and July 2014, 21 Micro-Tech® FC-SEMS (Nanjing Co., Republic of Korea) were placed in our hospital in 16 patients for inoperable, recurrent (after dilatation), and symptomatic benign airway stenosis. Their medical files were retrospectively reviewed in December 2014, with focus on stent’s tolerance and durability data.Results.Twenty-one stents were inserted: 13 for posttransplant left main bronchus anastomotic stricture, seven for postintubation tracheal stenosis, and one for postlobectomy anastomotic stricture. Positioning was easy for all of them. Stents were in place for a mean duration of 282 days. The most common complications were granulation tissue development (35%), migration (30%), and sputum retention (15%). Fifty-five % of the stents (11/20) had to be removed because of various complications, without difficulty for all of them. None of the patients had life-threatening complications.Conclusion.Micro-Tech FC-SEMS were easy to position and to remove. While the rate of complications requiring stent removal was significant, no life-threatening complication occurred. Further studies are needed to better define their efficacy and safety in the treatment of benign airway disease.

Summary Background Enterobacteriaceae are recognized as leading pathogens of healthcare-associated infections. Aim To report the investigation of a nosocomial outbreak of extended-spectrum β-lactamase-producing Enterobacter cloacae affecting cardiothoracic surgery patients in a Belgian academic hospital. Methods Cases were defined based on epidemiological and microbiological investigations, including molecular typing using repetitive element-based polymerase chain reaction and multi-locus sequence typing. Case–control studies followed by field evaluations allowed the identification of a possible reservoir, and the retrospective assessment of human and financial consequences. Findings Over a three-month period, 42 patients were infected or colonized by CTX-M-15-producing E. cloacae strains that belonged to the same clonal lineage. Acquisition mainly occurred in the intensive care unit (N = 23) and in the cardiothoracic surgery ward (N = 16). All but one patient had, prior to acquisition, undergone a cardiothoracic surgical procedure, monitored by the same transoesophageal echocardiography (TOE) probe in the operating room. Despite negative microbiological culture results, the exclusion of the suspected probe resulted in rapid termination of the outbreak. Overall, the outbreak was associated with a high mortality rate among infected patients (40%) as well as significant costs (€266,550). Conclusion The outbreak was indirectly shown to be associated with the contamination of a manually disinfected TOE probe used per-operatively during cardiothoracic surgery procedures, because withdrawal of the putative device led to rapid termination of the outbreak.

Introduction Prevalence and 1-year impact of right ventricular systolic dysfunction (RVSD) early after lung transplantation (LTx), in a population without pulmonary hypertension (PHT), is not well documented. In this retrospective study, we hypothesized that, as after heart Tx, occurrence of early RVSD after LTx in those patients (pts) would be associated with impaired 1-year survival.¹ Methods After ICU admission of LTx pts, we routinely perform a comprehensive transoesophageal echocardiographic (TOE) to check pulmonary veins’ patency. After exclusion of pts transplanted for PHT and of pts under ECMO, we retrospectively reviewed RV systolic data acquired during this TOE. At the time of TOE, all pts were mechanically ventilated. RVSD was defined based on visual assessment (RV dilation and/or RV hypokinesia) and RV fractional area change (FAC) Results From January 2004 to March 2018, 166 LTx pts underwent comprehensive TOE in ICU. Indications for LTx were COPD in 117 pts (70.5%), fibrosis in 25 (15.1%), cystic fibrosis in 7 (4.2%), bronchiectasis in 7 pts (4.2%) and other indications in 10 (6.0%). RV visual assessment was reported as abnormal in 56/166 pts (33.7%). RV FAC was reported in 112 pts and was Discussion Based on this retrospective TOE and single-center experience, prevalence of early RVSD after LTx, in a population without PHT, ranges from 34 to 39%, depending on the used criteria (visual assessment or RV FAC). However, occurrence of early RVSD after LTx was not associated with impaired 1-year survival.

Is Thrombin Time useful for the assessment of dabigatran concentrations? An in vitro and ex vivo study

The perioperative management of dabigatran is challenging, and recommendations based on activated partial thromboplastin time (aPTT) and thrombin time (TT) are unsatisfactory. Dedicated coagulation tests have limitations at plasma concentrations < 50 ng/ml. Therefore, a more sensitive test, which is available 24/7, is required. It was the aim of this study to investigate the performance of the Hemoclot Thrombin Inhibitors® LOW (HTI LOW) kit, a diluted thrombin time, and the STA® – ECA II (ECA-II) kit, a chromogenic variant of the ecarin clotting time, that were developed to measure low dabigatran concentrations, compared to reference dabigatran analysis by liquid chromatography tandem mass-spectrometry (LC-MS/MS). This study included 33 plasma samples from patients treated with dabigatran etexilate who had plasma concentrations < 200 ng/ml. HTI LOW and ECA-II were performed along with HTI, aPTT (STA®-C. K.Prest® and SynthasIL ®) and TT (STA® – Thrombin). All procedures were performed according to recommendations by the manufacturers. Linear (or curvilinear) correlations and Bland-Altman analyses were calculated. For free dabigatran concentrations < 50 ng/ml, the R2 of linear correlations were 0.69, 0.84 and 0.61, with HTI, HTI LOW and ECA-II, respectively. The R2 for TT, STA®-C. K.Prest® and SynthasIL® were 0.67, 0.42 and 0.15. For HTI, HTI LOW and ECA-II, Bland-Altman analyses revealed mean differences of –6 ng/ml (95 %CI: –25–14 ng/ml), 1 ng/ml (95 %CI: –18–19 ng/ml) and –1 ng/ml (95 %CI: –25–23 ng/ml), demonstrating that tests dedicated to measuring low concentrations are more accurate than HTI. In conclusion, the use of HTI LOW or ECA-II to assess low plasma dabigatran concentrations is supported by our findings.

Background Osteogenesis imperfecta is a genetic disorder of connective tissue causing mostly left-sided heart valves and aortic root pathologies, but a coronary artery involvement reflecting an increased sensitivity to cardiovascular risk factors is also suspected in this patient population. Case presentation We report a 38-year-old patient with an osteogenesis imperfecta and a typical presentation of an acute myocardial infarction. The coronary angiogram showed a coronary 3-vessel disease. The patient underwent a bypass grafting surgery with the internal mammary artery. The sternum was closed using four nitinol clips and had totally stabilized at 4 months with excellent bone healing. Conclusions With the successful clinical outcome in this patient severely affected by its osteogensis imperfecta, we underline the safe use of the LIMA, if precaution is taken towards the sternal bone, and its closure with nitinol clips.

Idarucizumab is a specific antagonist for dabigatran etexilate (DE). The recent market authorization of idarucizumab in Europe and the USA may reassure prescribers of DE, as it can increase the safety of the emergency management of patients taking this anticoagulant. However, idarucizumab use should be limited to specific indications to avoid unnecessary risks to patients and costs to healthcare systems. Areas covered: The authors provide an overview of idarucizumab development and its pharmacokinetic and pharmacodynamic properties. The results of the clinical phase III trial RE-VERSE AD and a review of recent case reports of idarucizumab use in emergency contexts are also discussed. Expert opinion: Although idarucizumab has shown clear efficacy in reversing dabigatran-induced coagulopathy, its overall effects on patient outcome have not been proven. Information regarding the clinical context in which patients on DE are admitted for emergency treatment, and accurate laboratory tests of dabigatran plasma level during reversal may inform selection and help with the follow-up of patients who may benefit from idarucizumab. Idarucizumab should be integrated into protocol for the emergency management of patients on DE. Furthermore, the benefit of idarucizumab in specific indications such as acute ischemic stroke should be investigated.

Dabigatran etexilate (DE), rivaroxaban, and apixaban are nonvitamin K antagonist oral anticoagulants (NOACs) that have been compared in clinical trials with existing anticoagulants (warfarin and enoxaparin) in several indications for the prevention and treatment of thrombotic events. All NOACs presented bleeding events despite a careful selection and control of patients. Compared with warfarin, NOACs had a decreased risk of intracranial hemorrhage, and apixaban and DE (110 mg BID) had a decreased risk of major bleeding from any site. Rivaroxaban and DE showed an increased risk of major gastrointestinal bleeding compared with warfarin. Developing strategies to minimize the risk of bleeding is essential, as major bleedings are reported in clinical practice and specific antidotes are currently not available. In this paper, the following preventive approaches are reviewed: improvement of appropriate prescription, identification of modifiable bleeding risk factors, tailoring NOAC's dose, dealing with a missed dose as well as adhesion to switching, bridging and anesthetic procedures. © 2014 Lessire Sarah et al.

Introduction Right ventricular (RV) diastolic dysfunction is known to be associated with increased mortality in heart failure or cardiac surgical patients (pts). However, after lung transplantation (LTx), the impact of early RV diastolic dysfunction on 1-year survival, in a population without pulmonary hypertension, is not well documented. Methods We routinely perform a comprehensive transoesophageal echocardiography (TOE) after ICU admission of LTx patients (pts) to check the pulmonary veins’ patency. After exclusion of pts transplanted for pulmonary hypertension and of pts under ECMO, we retrospectively reviewed the diastolic RV parameters acquired during this TOE. At that time, all pts were mechanically ventilated. RV diastolic function was explored by tricuspid peak early and late velocities (E and A waves) (pulsed-wave Doppler (PW) through the tricuspid valve), early diastolic peak velocity (Ea) of the lateral tricuspid annulus (PW-TDI), hepatic venous flow (HVF) pattern (PW Doppler), and characterized as normal or abnormal according to the algorithm validated by Shi et al. One-year survival status was recorded. Continuous variables are presented as median [interquartile range] and analysed with Mann-Whitney U test. Dichotomous variables are presented as numbers (%) and analysed with Chi-Squared test. Results From May 2008 to March 2018, RV diastolic data were available in 69 pts. Indications for LTx were COPD in 51 pts (73.9%), fibrosis in 12 (17.4%), bronchiectasis in 1 pt (1.5%) and other indications in 5 (7.2%). RV diastolic function was categorized as abnormal in 47pts. One-year survival rate was 72.3% (34/47) in the group with early RV diastolic dysfunction and 95.4% (1/22) in the group with normal RV diastolic function (P = 0.027). Discussion Based on these retrospective TOE data in this single-center experience, occurrence of early RV diastolic dysfunction after LTx seems to be associated with impaired 1-year survival. Further prospective data are needed to confirm these preliminary observations.

Introduction: Estimation of residual rivaroxaban plasma concentrations may be requested before invasive procedures and some patients at high thromboembolic risk will have a bridging therapy with heparins when rivaroxaban is interrupted. Objective: The objective of this study was to assess the performance of the STA-Liquid Anti-Xa assay (STA LAX) and the low and normal procedures of the Biophen Direct Factor Xa Inhibitors (DiXaI) assay, in patients with and without bridging with low-molecular-weight heparins (LMWHs). Materials and Methods: Seventy-nine blood samples were collected from 77 patients on rivaroxaban at CTROUGH or before an invasive procedure. Rivaroxaban plasma concentrations were estimated using Biophen DiXaI, Biophen DiXaI LOW, and STA LAX and compared to liquid chromatography coupled with mass spectrometry (LC-MS/MS) measurements. Stratifications were performed according to heparin bridging. Results: The Biophen DiXaI LOW and STA LAX showed better correlation with LC-MS/MS measurements than Biophen DiXaI in patients not bridged with LMWH (R: 0.97, 0.96, and 0.91, respectively). However, the performance of Biophen DiXaI LOW and STA LAX decreased when residual LMWH activity was present (R: 0.18 and 0.19 respectively) demonstrating that these tests are not specific to rivaroxaban. Conclusion: In patients not bridged with LMWH, we suggest to use the Biophen DiXaI LOW and STA LAX for the estimation of rivaroxaban concentrations

Objectif : Chez les patients severement denutris, un support nutritionnel preoperatoire permet de reduire l’impact pejoratif de la denutrition sur l’evolution postoperatoire. Un pre-requis indispensable est d’identifier cette denutrition. Nous avons voulu savoir si la consultation pre-anesthesique (non obligatoire en Belgique) etait un outil permettant d’atteindre ces objectifs de depistage preoperatoire chez des patients operes d’une chirurgie abdominale. Methode : Notre methode de travail s’est articulee en trois etapes. Apres avoir determine notre situation de depart, nous sommes intervenus en inserant le Nutritionnal risk screening (NRS) 2002 dans notre protocole de consultation informatise et en creant une procedure permettant de coupler notre consultation a celle de dietetique le meme jour. Nous avons ensuite analyse l’efficacite de nos interventions. Resultats : Nous avons recu 87,8 % des patients operes electivement d’une chirurgie abdominale a la consultation pre-anesthesique. Grâce a l’informatisation du NRS 2002, notre depistage nutritionnel est passe de 60,8 % a 86,1 %. Tout patient a risque de denutrition a ete refere le jour meme au service de dietetique pour une evaluation nutritionnelle et un support nutritionnel si necessaire. Cette procedure a reduit au maximum les retours des patients a l’hopital. Le delai moyen de 13 a 15 jours entre la consultation pre-anesthesique et la chirurgie etait suffisant pour mettre en place un support nutritionnel preoperatoire. Conclusion : La consultation pre-anesthesique est ainsi devenue un outil de depistage pour la prise en charge nutritionnelle preoperatoire.

Several direct oral anticoagulants (DOACs) are now widely used in the prevention and treatment of thromboembolic events. Unlike vitamin K antagonists, DOACs exhibit predictable pharmacokinetics and pharmacodynamics. DOACs are to be administered at fixed doses without routine coagulation monitoring. However, in some patient populations or specific clinical circumstances, measurement of drug exposure may be useful, such as in suspected overdose, in patients with a haemorrhagic or thromboembolic event during treatment with an anticoagulant, in those with acute renal failure, or in patients who require urgent surgery. This article provides practical guidance on laboratory testing of DOACs in routine practice and summarizes the influence of DOACs on commonly used coagulation assays.

In the paper titled “preventive strategies against bleeding due to nonvitamin K antagonist oral anticoagulants,” the authors’ given first and last names were inverted. Here we provide the right authors’ information as shown above.[This corrects the article on p. 616405 in vol. 2014.]

Dabigatran etexilate (DE), rivaroxaban, and apixaban are nonvitamin K antagonist oral anticoagulants (NOACs) that have been compared in clinical trials with existing anticoagulants (warfarin and enoxaparin) in several indications for the prevention and treatment of thrombotic events. All NOACs presented bleeding events despite a careful selection and control of patients. Compared with warfarin, NOACs had a decreased risk of intracranial hemorrhage, and apixaban and DE (110 mg BID) had a decreased risk of major bleeding from any site. Rivaroxaban and DE showed an increased risk of major gastrointestinal bleeding compared with warfarin. Developing strategies to minimize the risk of bleeding is essential, as major bleedings are reported in clinical practice and specific antidotes are currently not available. In this paper, the following preventive approaches are reviewed: improvement of appropriate prescription, identification of modifiable bleeding risk factors, tailoring NOAC’s dose, dealing with a missed dose as well as adhesion to switching, bridging and anesthetic procedures.

BACKGROUND Dabigatran etexilate has received its market authorization for various indications worldwide. It was developed to be used in fixed dose regimens without the need of regular monitoring. However, the perioperative management of dabigatran could require an assessment of the drug plasma levels to ensure a safe use of the product, especially in absence of specific antidotes. The EMA stated that dabigatran concentrations under 48 ng/mL should be reached before invasive intervention. The GIHP put the threshold at 30 ng/mL. Therefore, a specific laboratory assay, accurate in the low concentration range, easily available and performable 24h/7 is requested but, until now, all coagulation tests dedicated to the measurement of plasma dabigatran concentrations showed a lower limit of quantitation from 30 to 50 ng/mL. This limits their perioperative utility and the thrombin time (TT) is currently presented as an alternative due to its very high sensitivity to dabigatran. This interesting approach has limitations because TT is affected by several analytical and biological variables that could lead to misinterpretations and expose the patient at riskier hemostatic conditions. In this study, we propose to investigate the performance of two coagulation tests (the Hemoclot Thrombin Inhibitors LOW (HTI LOW) (Hyphen BioMed) and the Ecarin Chromogenic Assay II (ECA-II) (Diagnostica Stago)) specifically developed to measure low plasma dabigatran concentrations and to compare their results with a reference LC-MS/MS. We also assessed the performance of the standard procedure of HTI and TT. MATERIALS AND METHODS Thirty-three plasma samples of patients treated with dabigatran etexilate for stroke prevention in non-valvular atrial fibrillation, were included in the study. Plasma samples were taken randomly and included after a first screening using the HTI to select plasma concentrations For HTI, tested plasma was diluted 1:8 in Owren-Koller® buffer. Fifty μl of tested plasma were mixed with 100 μl of normal pooled plasma and were incubated during 240 sec. One hundred μl of highly purified human thrombin pre-incubated at 37°C was then added to start the reaction. For HTI LOW, the dilution of the sample was reduced to 1:2 and specific calibrators at lower concentrations were used. For ECA-II, tested plasma was diluted 1:5 in Owren-Koller® buffer. Fifty μl of tested plasma were mixed with 140 μl of prothrombin and then 70 µl of chromogenic substrate were added and incubated during 240 sec. Seventy μl of ecarin pre-incubated at 37°C were then added to start the reaction. Thrombin time was performed using Thrombin Time® reagent 1.5NIH (Diagnostica Stago) and the limit of measurement was extended to 300 sec. All of these procedures were performed on a STA-R Evolution® coagulometer (Diagnostica Stago). RESULTS AND DISCUSSION The plasma concentrations ranged from 0 to 200 ng/mL as provided by LC-MS/MS measurements. Among these samples, 17 were between 0 and 50 ng/mL. Linear correlation, Spearman correlation and Bland-Altman analyses versus LC-MS/MS are provided in Figure 1, for assays that express results in ng/mL, i.e. HTI, HTI LOW and ECA-II. For TT, the relation is described by linear correlation. Our results show that HTI LOW performs better than HTI and ECA-II on the whole concentration range providing closer correlation and a lower systematic difference compared to LC-MS/MS. For concentrations below 50 ng/mL HTI LOW and ECA-II reveal similar systematic difference with higher 95% CI for ECA-II and perform better than HTI to estimate plasma concentrations. Thrombin time is less useful than dedicated assays to provide an estimation of the pharmacodynamics of dabigatran. For concentrations above 50 ng/mL it often exceeds the limit of measurement, i.e. 120 sec as defined by the manufacturer, and is influenced by the level of fibrinogen. However, it gives an acceptable correlation for concentration below 50 ng/mL. This may help the biologist to choose which test to use to avoid unnecessary costs and ensure the use of the more accurate dedicated assay to estimate the plasma concentrations. When TT is lower than 120 sec, HTI LOW or ECA-II should be preferred to HTI. CONCLUSION We recommend the use of specific coagulation assays to assess the dabigatran plasma concentrations before invasive procedure. Thrombin time may guide the biologist on the dedicated coagulation test to perform if he uses the HTI platform. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.